The long term goals of this research are to discover novel peptidic opioid ligands with unique biological profiles at opioid receptors, including potent analgesics, but with no or minimal addiction potential, and none of the toxic side effects of current opioids, and that cross the blood-brain barrier (BBB). For this purpose we are developing a comprehensive approach that involves; computer assisted design of novel biostable ligands; asymmetric synthesis and macrocyclic synthesis of novel amino acids and peptides with unique conformational and topographical properties; development of opioid peptide conjugates and prodrugs with unique properties; and computer aided design and other biophysical studies of the conformational, topographical and dynamic properties of the novel compounds. The specific aims of reach these goals include: 1) Exploitation and development of our systematic approach to ligand design which includes: stimultaneous design of ligands with high potency and unique biological profiles, selectivity for opioid receptors, and stability against proteolytic degradation; prodrug design of these ligands for specific cleavage in the brain or at the BBB to the highly potent ligand; utilization of built in chemical-physical properties for penetration of the BBB; and utilization of peptide-conjugates to utilize transport mechanisms at the BBB; 2) Une of computer assisted modeling, NMR and other biophysical methods to help optimize design of analogues of cyclic enkephalins such as DPDPE, Deltorphins, and Dermenkephalins that will cross the BBB; 3) Optimization of potency and biostability of biphalin and glycopeptide analogues; 4) Optimization of design of biphalin analogues with exceptional efficacy that can cross the BBB; 5) Exploration of methods of asymmetric synthesis of unusual amino acids constrained at khi1 and khi2 torsional angles that will provide opioid ligands with unique opioid receptor potency and selectivity, analogesic efficacy, and passage through BBB; 6) Close collaboration with biophysical and biological colleagues to produce more stable, bioavailable and efficacious delta ligands; 7) Comprehensive conformational analysis studies of carefully chosen analogues using NMR and other biophysical methods to aid in design; 8) Use of homology modeling to develop 3D models of the recently coloned delta receptors that can be evaluated by site specific mutagenesis of receptors and by site specific design or ligands.